Fenofibrate microparticles

ABSTRACT

Fenofibrate microparticles are prepared using a combination of surface modifiers with a phospholipid. Particle size growth and stability are controlled while significantly smaller sized fenofibrate particles are produced.

[0001] This application is a continuation-in-part of application Ser.No. 09/218,080 filed Dec. 22, 1998 which is a continuation-in-part ofapplication Ser. No. 08/701,483 filed Aug. 22, 1996, now U.S. Pat. No.______. The disclosures of these applications are hereby incorporated byreference.

[0002] This invention relates to compositions and procedures that yieldsub-micron and micron stable particles of fenofibrate. The compositionsof this invention include combinations of natural or syntheticphospholipids, and one or more nonionic, anionic or cationic surfactantscoated or adhered onto the surfaces of the fenofibrate particles. Thecombination of phospholipids and surfactants allows the formation andstabilization of the sub-micron and micron size compound particles bymodification of the surface and changes in hydrophilic, lipophilic andelectrostatic interactions between particles.

BACKGROUND OF THE INVENTION

[0003] Fenofibrate is a prodrug that immediately after absorption ishydrolyzed by tissue and plasma esterases to its active majormetabolite, fenofibric acid. Fenofibric acid is responsible for thepharmacological activity and its plasma half-life is about 20 hours.Fenofibrate is practically insoluble in water, it is poorly and variablyabsorbed and has to be taken with food.

[0004] Fenofibrate was first available in a pharmaceutical dosage form(Lipanthyl® also marketed under the trademarks Lipidil® and Lipantil®)consisting of a hard gelatin capsule containing fenofibrate, lactose,pregelatinized starch and magnesium stearate. After oral administration,during a meal, about 60% of the dose of this conventional form iseffectively absorbed and found in the blood as fenofibric acid (Weil etal., The metabolism and disposition of 14C-fenofibrate in humanvolunteers, Drug. Metabol. Dispos. Biol. Fate. Chem., 18 (1990)115-120).

[0005] Historically, in order to improve the intestinal absorption,another pharmaceutical dosage form was introduced (Lipanthyl® 67M and200M, also marketed under the trademarks Lipidil Micro®, Lipantil®Microand Tricor™). European Patent Application 330,532 and U.S. Pat. No.4,895,726 disclose a fenofibrate composition in which the fenofibratepowder is co-micronized with a solid wetting agent. Sodium laurylsulfate is described as the wetting agent of choice. The co-micronizedpowder so obtained is mixed with capsule filling excipients such aslactose, starch, cross-linked polyvinyl pyrrolidone and magnesiumstearate. A study comparing this formulation (Lipidil Micro®) to theconventional form (Lipidil®) had shown statistically significantincrease in bioavailability with the former.

[0006] However, co-micronization of the active drug fenofibrate with thewetting agent sodium lauryl sulfate, although necessary, has severaldrawbacks such as irritation of mucosal membranes of thegastrointestinal tract. In addition, micronization is a time consumingand costly operation and the filling of hard gelatin capsules with amicronized powder is a difficult operation when taking into account thepossibility of weight variation due to poor homogeneity.

[0007] European Patent Application 724,877 describes fenofibrate powderco-micronized with a wetting agent in association with a vitamin Ecomponent (tocopherol and/or its organic acid ester) for treating orpreventing disorders associated with lipoprotein oxidation.

[0008] U.S. Pat. No. 4,800,079 relates to a medicinal composition in theform of granules with controlled release of fenofibrate. Each granuleincludes an inert core, a layer based on fenofibrate and a protectivelayer. Fenofibrate is present in the form of crystalline microparticlesof dimensions not greater than 30 μm.

[0009] U.S. Pat. No. 4,961,890 relates to a process for preparing acontrolled release formulation containing fenofibrate in an intermediatelayer in the form of crystalline microparticles (<30 μm in diameter)within a multilayer inert matrix.

[0010] U.S. Pat. No. 5,545,628 relates to a pharmaceutical compositionfor treating hyperlipidemia or hypercholesterolemia or both in a mammal,by providing an effective amount of each of fenofibrate and an excipientincluding one or more polyglycolyzed glycerides (generally mixtures ofknown monoesters, diesters and triesters of glycerols and knownmonoesters and diesters of polyethylene glycols). The polyglycolyzedglycerides may be obtained by partial transesterification oftriglycerides with polyethylene glycol or by esterification of glyceroland polyethylene glycol with fatty acids.

[0011] European Patent Application 757,911 relates to a fenofibratepharmaceutical dosage form in which fenofibrate is in solution indiethylene glycol monoethyl ether (EMDG) which is a non ionicsurfactant.

[0012] Current technology for delivering insoluble drugs as described inU.S. Pat. Nos. 5,091,188; 5,091,187 and 4,725,442 focuses on (a) eithercoating small drug particles with natural or synthetic phospholipids or(b) dissolving the drug in a suitable lipophilic carrier and forming anemulsion stabilized with natural or semisynthetic phospholipids. One ofthe disadvantages of these formulations is that certain drug particlesin suspension tend to grow in size over time because of the dissolutionand reprecipitation phenomenon known as the Ostwald ripening or particlegrowth. The solvent becomes saturated with solute, the larger particlesgrow at the expense of smaller particles which preferentially solubilize[Luckham, Pestic. Sci., (1999) 25, 25-34].

[0013] As used herein, “micro” refers to a particle or collection ofparticles having diameter of from nanometers to micrometers.Microparticles, as used herein, refer to solid fenofibrate particles ofirregular, non-spherical or spherical shapes with combinations ofnatural or synthetic phospholipids, and one or more nonionic, anionic orcationic surfactants coated or adhered onto the surfaces of thefenofibrate particles. Formulations containing these fenofibratemicroparticles provide specific advantages over the unformulated,non-micronized, or “conventional” micronized particles, which includeimproved oral bioavailability as absorbed from the GI tract.

DESCRIPTION OF THE INVENTION

[0014] The present invention focuses on preparing submicron to micronsize fenofibrate particles using a combination of surface modifier(s)with a phospholipid, and how the growth of particle size, and hencestorage stability, is controlled by adding a combination of surfacemodifier(s) with a phospholipid to the formulation.

[0015] The use of a surface modifier or combination of surface modifiersin addition to a phospholipid is characterized by its ability to resultin volume weighted mean particle size values that are (i) approximately50% smaller than what can be achieved using phospholipid alone withoutthe use of a surfactant with the same energy input, and (ii) providecompositions resistant to particle size growth on storage. Whileresistance to particle size growth on storage was an objective of thisinvention we were surprised to observe a significant reduction inparticle size with the addition of the surfactant. In order to achievethe advantages of the present invention it is necessary that thephospholipid and the surfactant both be present at the time of particlesize reduction or precipitation.

[0016] Another aspect of the present invention includes free-flowingpowders of fenofibrate as well as solid dosage forms of these powders,for instance in the form of compressed tablets and the like.Surprisingly we have found that microparticulate formulations exhibitenhanced stability and bioavailability as illustrated in the data thatfollows.

[0017] Although we do not wish to be bound by any particular theory, itappears that these surface modifiers generally, that is phospholipidsand one or more surfactants, adsorb to the surfaces of fenofibrate, andmodify the surfaces to allow smaller particle formation and stailize theformed micoparticles. The concentrations of surface modifiers used inthe process described here are normally above their critical micelleconcentrations (CMC) and hence facilitate the formation of sub-micron tomicron particles by stabilizing the particles.

[0018] Phospholipid and surface modifier(s) are adsorbed onto thefenofibrate particle surfaces in sufficient quantity to retard particlegrowth, reduce the initial average particle size of from 5 to 100 μm tomicron and submicron size particles by one or combination of methodsknown in the art, such as sonication, homogenization, milling,microfluidization, precipitation or recrystallization or precipitationfrom supercritical fluid, and maintain sub-micron and micron sizeparticles on subsequent storage as suspension or solid dosage form.

[0019] The concentration of phospholipid or surface modifier in thesuspension or solid dosage form can be present in the range of 0.1 to50%, preferably 0.2 to 20%, and more preferably 0.5 to 10%.

[0020] The formulations prepared by this invention may be dried, e.g.,by lyophilization, fluid or spray drying, into powders, which can beresuspended or filled into capsules or converted into granules ortablets with the addition of binders and other excipients known in theart of tablet making.

[0021] The phospholipid may be any natural or synthetic phospholipid,for example phosphatidylcholine, phosphatidylethanolamine,phosphatidylserine, phosphatidylinositol, phosphatidylglycerol,phosphatidic acid, lysophospholipids, sphyngomyelin, egg or soybeanphospholipid or a combination thereof. The phospholipid may be salted ordesalted, hydrogenated or partially or fully hydrogenated natural, semisynthetic or synthetic. Examples of commercially available phospholipidsinclude but are not limited to egg phospholipids P 123 (Pfanstiehl),Lipoid E80 (Lipoid); and hydrogenated soy phospholipids Phospholipon 90Hand 100H (Natterman) and 99% pure soy or egg phosphatidyl choline(Avanti Polar Lipids).

[0022] Examples of some suitable surface modifiers include: (a) naturalsurfactants such as casein, gelatin, tragacanth, waxes, enteric resins,paraffin, acacia, gelatin, cholesterol esters and triglycerides, (b)nonionic surfactants such as polyoxyethylene fatty alcohol ethers,sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitanesters, glycerol monostearate, polyethylene glycols, cetyl alcohol,cetostearyl alcohol, stearyl alcohol, poloxamers, polaxamines,methylcellulose, hydroxycellulose, hydroxy propylcellulose, hydroxypropylmethylcellulose, noncrystalline cellulose, polyvinyl alcohol,polyvinylpyrrolidone, and synthetic phospholipids, (c) anionicsurfactants such as potassium laurate, triethanolamine stearate, sodiumlauryl sulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctylsodium sulfosuccinate, negatively charged phospholipids (phosphatidylglycerol, phosphatidyl inositol, phosphatidylserine, phosphatidic acidand their salts), and negatively charged glyceryl esters, sodiumcarboxymethylcellulose, and calcium carboxymethylcellulose, (d) cationicsurfactants such as quaternary ammonium compounds, benzalkoniumchloride, cetyltrimethylammonium bromide, chitosans andlauryldimethylbenzylammonium chloride, (e) colloidal clays such asbentonite and veegum or a combination thereof. A detailed description ofthese surfactants may be found in Remington's Pharmaceutical Sciences,and Theory and Practice of Industrial Pharmacy, Lachman et al, 1986.

[0023] More specifically, examples of suitable surface modifiers includeone or combination of the following surfactants: polaxomers, such asPluronic™ F68, F108 and F 127, which are block copolymers of ethyleneoxide and propylene oxide available from BASF, and poloxamines, such asTetronic™ 908 (T908), which is a tetrafunctional block copolymer derivedfrom sequential addition of ethylene oxide and propylene oxide toethylene-diamine available from BASF, Triton™ X-200, which is an alkylaryl polyether sulfonate, available from Rohm and Haas. Tween 20, 40, 60and 80, which are polyoxyethylene sorbitan fatty acid esters, availablefrom ICI Specialty Chemicals, polyoxyethylene stearate (Myrj 52)available from ICI Specialty Chemicals, Carbowax™ 3550 and 934, whichare polyethylene glycols available from Union Carbide, hydroxypropylmethylcellulose, dimyristoyl phosphatidylglycerol sodium salt,sodium dodecylsulfate, sodium deoxycholate, and cetyltrimethylammoniumbromide. In some cases preferably at least two surfactants are used. Ina preferred aspect of the invention, when free-flowing formulations aredesired, the surfactant(s) will itself be a powder.

[0024] It is thought that some of the functions of the second surfacemodifier(s) as it relates to this invention are (a) allowing theformation of microparticles about 50% or smaller of the size producedwith phospholipid alone, (b) suppressing the process of Ostwald Ripeningand therefore maintaining the particle size, (c) increasing the storagestability, minimizing sedimentation, and decreasing the particle growthduring lyophilization and reconstitution; (d) adhering or coating firmlyonto the surfaces of water-insoluble drug particles and thereforemodifying the interfaces between the particles and the liquid in theresulting formulations; (e) increasing the interface compatibilitybetween water-insoluble drug particles and the liquid; and (f) possiblyorienting preferentially themselves with the hydrophilic portionsticking into the aqueous solution and the lipophilic portion stronglyadsorbed at the water-insoluble drug particle surfaces.

[0025] The most advantageous surface active agent for fenofibrate isillustrated in the examples that follow and/or as will be apparentfollowing empirical tests to identify the surfactant or surfactantsystem/combination resulting in the requisite particle size and particlesize stability on storage over time.

[0026] Various procedures can be used to produce these stable micron andsub-micron size fenofibrate particles including mixing the fenofibratewith phospholipid and surfactant(s) followed by sonication, milling,homogenization, microfluidization; or precipitating from a solution ofthe substance using antisolvent and solvent precipitation in thepresence of the phospholipid and surfactant(s). Mannitol and otheragents may be added to adjust the final formulation to isotonicity aswell as acting as a stabilizing aid during drying.

[0027] Unless otherwise specified, all parts and percentages reportedherein are weight per unit volume (w/v), in which the volume in thedenominator represents the total volume of the system. Diameters ofdimensions are given in millimeters (mm=10⁻³ meters), micrometers(μm=10⁻⁶ meters), nanometers (nm=10⁻⁹ meters) or Angstrom units (=0.1nm). Volumes are given in liters (L), milliliters (mL=10⁻³ L) andmicroliters (μL=10⁻⁶L). Dilutions are by volume. All temperatures arereported in degrees Celsius. The compositions of the invention cancomprise, consist essentially of or consist of the materials set forthand the process or method can comprise, consist essentially of orconsist of the steps set forth with such materials. The followingexamples further explain and illustrate the invention:

[0028] The following microparticle-fenofibrate formulations wereprepared either by using Microfluidizer® model 110EH (MicrofluidicsCorp., Newton, Mass.) or Avestin model C5 (Ottawa, Canada).

[0029] A premix of the formulation was prepared by placing theingredients in an appropriate size vessel with the required amount ofwater and mixed with a hand held homogenizer. The premix so formed wasthen placed in the inlet reservoir of the homogenizer and passing theoutlet flow through a thermostatically controlled cooler to control theinlet temperature. The premix was then pumped through the homogenizer at18,000-20,000 psi. The homogenization process can either be done bydiscrete passes or in continuous mode. For the sake of comparison, allformulations (except Example 2) were homogenized for 90 passes inAvestin homogenizer. The formulation in example 2 was prepared in aMicrofluidizer® with using approximately 50 passes at full pressure. Theformulations were harvested and particle size and other parametersmeasured. The particle size determination was performed with MalvernMastersizer model Micro-Plus (Southborough, Mass.). The particle sizedata are presented as volume weighted mean particle size.

[0030] The composition and concentration of excipients of variousmicroparticle fenofibrate formulations are listed below. The amount ofexcipients used is expressed as percent (w/w): Example 1 Fenofibrate10.0 Phospholipon 100 H 2.0 Tween 80 2.0 Mannitol 5.5 Mean particlesize: 0.85 μm Example 2 Fenofibrate 10.0 Phospholipon 100 H 2.0 Tween 802.0 Mannitol 10.0 Mean particle size: 1.02 μm Example 3 Fenofibrate 10.0Phospholipon 100 H 2.0 PVP 30 1.5 Mannitol 5.5 Mean particle size: 1.28μm Example 4 Fenofibrate 10.0 Phospholipon 100 H 2.0 Myrj 52 1.5Mannitol 5.5 Mean particle size: 1.21 μm Example 5 Fenofibrate 10.0Phospholipon 100 H 2.0 Poloxamer 188 1.5 Mannitol 5.5 Mean particlesize: 1.12 μm

EXAMPLE A

[0031] For the purpose of comparison (not according to the invention)using only a phospholipid, (without the second surface modifier, Tween80), fenofibrate particles were also prepared using the same procedureas Example 1: Fenofibrate 10.0 Phospholipon 100 H 2.0 Mannitol 5.5 Meanparticle size: 3.17 μm

[0032] A comparison of the resulting mean particles size of the finalformulations in Examples 1 to 5, inclusive, with Example A demonstratethe effect of adding the second surface modifier on the final particlesize. Also, it was observed that the use of a second surface modifierhelps to eliminate the thick slurry produced when Phospholipon 100H isused alone as in Example A.

EXAMPLE 6

[0033] Oral Bioavailability of Fenofibrate Microparticles in HumanSubjects.

[0034] The Fenofibrate composition used in Example 2 was tested in ahuman volunteers study. The study consisted of oral administration ofthe fenofibrate formulation to eight human volunteers in a single dosecrossover design, using the marketed formulation as a reference. Thedose administered was 67 mg. Blood samples were collected before andafter each administration at various time points over 120 hours.

[0035] The drug concentration in blood samples was determined byhigh-pressure liquid chromatography by monitoring for the level of themetabolite, fenofibric acid. The pharmacokinetic results are presentedin Table 1 and demonstrate the superior bioavailability of thefenofibrate formulation over the commercially available product. TABLE 1C_(max) and AUC₀−inf for Fenofibric Acid C_(max) AUC_(0−inf) (ng.ml⁻¹)(ng.ml⁻¹.h) Fenofibrate microparticles (67 mg) 2528 57235 Commerciallyavailable fenofibrate 1372 38629 (67 mg) product Dunnett's t-test (logtransformed data) p < 0.05 p < 0.05

What is claimed is:
 1. A pharmaceutical composition comprisingfenofibrate containing microparticles produced by applying energy tofenofibrate in the presence of phospholipid and surface modifier(s),said microparticles consisting essentially of fenofibrate, aphospholipid and at least one surface modifier in which the surfacemodifier or surface modifiers provide volume-weighted mean particle sizevalues of the water-insoluble compound about 50% smaller than particlesproduced in the presence of a phospholipid and without the presence ofthe surface modifier using the same energy input.
 2. A pharmaceuticalcomposition comprising fenofibrate containing microparticles produced byapplying energy to fenofibrate in the presence of phospholipid andsurfactant surface modifier, said microparticles consisting essentiallyof fenofibrate, a phospholipid and at least one non-ionic, anionic orcationic surfactant, in which the surfactant or surfactants providevolume-weighted mean particle size values of the water-insolublecompound about 50% smaller than particles produced in the presence of aphospholipid and without the presence of the surfactant using the sameenergy input.
 3. A hard or soft gel capsule formulation comprising thecomposition of claim 1 or
 2. 4. A suspension, spray-dried powder,lyophilized powder granules, capsules or tablets of the composition ofclaim
 2. 5. The composition of claim 1 or claim 2 wherein the surfacemodifier is a polyoxyethylene sorbitan fatty acid ester, a blockcopolymer of ethylene oxide and propylene oxide, polyoxyethylenestearate a tetrafunctional block copolymer derived from sequentialaddition of ethylene oxide and propylene oxide to ethylenediamine, analkyl aryl polyether sulfonate, polyethylene glycol, hydroxypropylmethylcellulose, sodium dodecylsulfate, sodium deoxycholate,cetyltrimethylammonium bromide or combinations thereof.
 6. Thecomposition of claim 1 or claim 2 wherein at least two surfactants areused.
 7. The process of claim 1 or 2 wherein the phospholipid is of eggor plant origin or semisynthetic or synthetic in partly or fullyhydrogenated form or in a desalted or salt form such asphosphatidylcholine, or dimyristoyl phosphatidylglyerol sodium salt,phosphatidylethanolamine, phosphatidylserine, phosphatidic acid,lysophospholipids or combinations thereof.
 8. In a process of preparingfenofibrate microparticles comprising reducing the particle size bysonication, homogenization, milling, microfluidization andprecipitation, or recrystallization and precipitation of the fenofibrateusing antisolvent and solvent precipitation or precipitation fromsupercritical fluids the improvement comprising the steps of: (1) priorto or during particle size reduction, mixing the fenofibrate particleswith (a) a natural or synthetic phospholipid and (b) at least onenon-ionic, anionic or cationic surfactant, and thereafter (2) applyingenergy to the mixture sufficient to produce volume-weighted meanparticle size values of fenofibrate about 50% smaller than particlesproduced without the presence of the surfactant using the same energyinput.
 9. A process of stabilizing fenofibrate microparticles andpreventing particles from aggregating or flocculating by coating oradhering onto the surfaces of the fenofibrate particles a mixture of aphospholipid together with at least one non-ionic, anionic or cationicsurfactant, the process comprising the steps of: (1) mixing saidparticles with a phospholipid and at least one non-ionic, anionic orcationic surfactant, and thereafter (2) applying energy to the mixturesufficient to produce volume-weighted mean particle size values of saidcompound about 50% smaller than particles produced without the presenceof the surfactant using the same energy input.
 10. The process of claim8 or 9 wherein the phospholipid is of egg or plant origin orsemisynthetic or synthetic in partly or fully hydrogenated form or in adesalted or salt form such as phosphatidylcholine, or dimyristoylphosphatidylglyerol sodium, salt, phosphatidylethanolamine,phosphatidiylserine, phosphatidic acid, lysophospholipids, orcombinations thereof.
 11. The process of claim 8 or 9 wherein thesurfactant is a polyoxyethylene sorbitan fatty acid esterpolyoxyethylene stearate, a block copolymer of ethylene oxide andpropylene oxide, a tetrafunctional block copolymer derived fromsequential addition of ethylene oxide and propylene oxide toethylenediamine, an alkyl aryl polyether sulfonate, polyethylene glycol,hydroxy propylmethylcellulose, sodium dodecylsulfate, sodiumdeoxycholate, cetyltrimethylammonium bromide or combinations thereof.12. The process of claim 8 or 9 wherein at least two surfactants areused.
 13. The process of claim 8 or 9 wherein the surfactant is presentabove the critical micelle concentration.
 14. A pharmaceuticalcomposition comprising microparticles prepared by the process of claim8.
 15. A pharmaceutical composition comprising microparticles producedby the process of claim 9